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Spastic tetraplegia and axial hypotonia (STAHP) associated with biallelic SOD1 deficiency is a recently described neurological disorder affecting children. Five studies have described a total of nine cases thus far, all characterized by the onset of progressive spastic tetraplegia beginning before 2 years of age. All but two of these cases are associated with homozygosity for the same genetic variant (NM_000454.4:c.335dupG; NP_000445.1:p.Cys112Trpfs*11) that leads to a non-functional enzyme product. More recently, a homozygous 3-base pair in-frame deletion (NM_000454.5: c.357_357+2delGGT) and a truncating frameshift variant (NM_000454.5: c.52_56del5ins154) in SOD1 have been described in similarly affected patients lacking SOD1 activity. Here we expand on the neurological and extra-neuronal phenotypes of STAHP in a patient with a novel homozygous SOD1 variant predicted to result in disrupted calcium- and zinc-binding activity of the encoded enzyme. We describe a 19-year-old male born to consanguineous parents who is homozygous for an NM_000454.4:c.369_371del SOD1 variant. The patient had progressive neuromuscular degeneration with onset before 1 year of age, consistent with a diagnosis of STAHP. Brain MRI at 7 years of age showed cerebellar atrophy, as has previously been described in this condition, as well as small optic nerves and a hypoplastic optic chiasm, which have not been reported previously. Our patient also exhibited clinical features of immune dysregulation with treatment-refractory inflammatory bowel disease, asthma, recurrent infections, and dermatitis. Overall, the early-onset progressive neurological disorder in our patient, found in association with homozygosity for an SOD1 variant that is predicted to result in impaired function of the transcribed protein, is consistent with a diagnosis of STAHP. Our patient also demonstrates optic atrophy and disrupted immune homeostasis, which have not been previously described as part of this condition. Taken together with previous case studies in children carrying loss-of-function variants of SOD1, this case highlights a possible role for antioxidant therapy in slowing disease progression in patients lacking SOD1 activity. These cases also draw attention to the need for careful consideration of possible harmful neuronal and extra-neuronal complications of proposed SOD1 knockdown therapies against ALS., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis. Methods We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. Results All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity. Conclusions This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency.

Background: Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis.Methods: We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population.Results: All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity.Conclusions: This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency. [ABSTRACT FROM AUTHOR]